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EDITORIALS |
From the Sydney Melanoma Unit, Royal Prince Alfred Hospital; and Department of Surgery, University of Sydney, Sydney, New South Wales, Australia.
Correspondence: Address correspondence to: John F. Thompson, MD, The Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, NSW 2050, Australia; Fax: 61-2-95506316; E-mail: john{at}mel.rpa.cs.nsw.gov.au
A fundamentally important but so far unanswered question is addressed in the article by Essner et al.1 in this issue of the Annals of Surgical Oncology. The question is whether regional lymph node status is of prognostic relevance in patients with thick (
4 mm) primary melanomas? A second and clinically even more important question arising from the first is whether surgical removal of positive regional lymph nodes influences the outcome for such patients?
Several previous studies have examined these questions by analyzing results for patients with thick melanomas who have undergone either elective lymph node dissection (ELND) or sentinel node (SN) biopsy with complete lymph node dissection (CLND) of regional nodes if a positive SN node has been found. Almost all of these studies have demonstrated that the patients whose regional lymph nodes are free of metastatic disease have a much better prognosis than those with involved regional nodes. Gershenwald et al.,2 for example, reported results for 126 patients with thick primary cutaneous melanomas who underwent lymphatic mapping and SN biopsy. They found that SN status was the most powerful predictor of overall survival on both univariate and multivariate analyses.
Cherpelis et al.3 studied 201 patients with melanomas > 3.0 mm in thickness. A substantial and statistically significant difference in 3-year disease-free survival between SN-positive and SN-negative patients was found (37% vs. 73%; P = .02). The overall 3-year survival for SN-positive patients was less than it was for SN-negative patients (70% vs. 82%), but the difference failed to reach statistical significance (P = .08). Multivariate analysis was not performed in this study.
More recently, Salti et al.4 have reported results for 151 patients with melanomas 4 mm in Breslow thickness. These authors found that on multivariate analysis the status of regional lymph nodes (as determined by ELND) was the factor most predictive of overall survival (P = .003) and disease-free survival (P = .009). The 5-year overall survival figures for patients who were node positive and node negative were 35% and 61%, respectively. For disease-free survival, these figures were 35% and 56%, respectively.
The results reported by Essner et al. are surprising in light of the above studies because they found that regional lymph node status (as determined by lymphatic mapping and SN biopsy) did not predict overall survival outcome for patients with thick primary melanomas, although SN status was predictive of disease-free survival in these patients. The study involved 113 patients treated at the John Wayne Cancer Institute between 1985 and 2000.
For several decades there has been controversy over the management of patients who present with a primary melanoma and clinically negative regional lymph nodes. The ongoing debate has been particularly concerned with patients who have had intermediate-thickness melanomas. For patients with thick primary melanomas, however, most centers have embraced the philosophy that treatment of the regional lymph nodes is not justified because the prognosis is universally poor. Nevertheless, since Reintgen et al. reviewed this issue in 1998,5 the results of the studies outlined above have indicated that long-term survival is in fact achieved in many patients with thick primary melanomas. Supporting this, analysis of a large data set from multiple melanoma treatment centers worldwide undertaken to revise the American Joint Committee on Cancer Staging system for melanoma6 indicated 5-year survival rates of 67.4% and 47.1% for patients with localized disease and with nonulcerated and ulcerated lesions >4 mm thick (T4N0M0), respectively. Thus, the attitude of therapeutic nihilism which has prevailed in many melanoma treatment centers in relation to patients with thick primary melanomas may not be justified.
In an attempt to shed further light on this vexed question, we reviewed the experience of the Sydney Melanoma Unit (SMU) in patients with primary cutaneous melanomas 4 mm in thickness who underwent lymphatic mapping and SN biopsy between 1993 and 2001. Of 1711 SN biopsy procedures performed at the SMU during this period, 172 were undertaken in patients who had melanomas of this thickness and who had clinically negative regional lymph nodes (i.e., stage II according to the 2002 American Joint Committee on Cancer/International Union Against Cancer staging system). Patients with multiple primary lesions were excluded. Also excluded were patients in whom the SN biopsy was performed as part of an ELND (mainly those SN biopsies performed during the "learning phase" of the technique) and those whose SN biopsy was not performed as part of their first definitive treatment but more than 2 months from primary lesion diagnosis (most commonly after a recurrence had developed). All histologic specimens (of both primary lesions and nodes) were reviewed by SMU pathologists, highly experienced in the diagnosis and assessment of melanocytic lesions and lymphatic metastases. Routine immunohistochemistry was performed on all SN biopsy specimens but not on CLND specimens.
Our findings in this, the largest cohort of patients with thick primary melanomas and undergoing SN biopsy reported to date, were remarkably similar to the results reported by Gershenwald et al.2 and were also in agreement with the studies by Cherpelis et al.3 and Salti et al.4 (although the latter two studies were not directly comparable). Table 1 documents our findings and those of Gershenwald et al. for comparison with those of Essner et al. Figures 1 and 2 illustrate the disease-free and overall survival curves for SMU patients with thick melanomas and either positive or negative SNs. On multivariate analysis of data from the SMU series, the status of the regional lymph nodes was the dominant prognostic factor for both disease-free survival (P = .00018) and overall survival (P = .0016).
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Before the introduction of lymphatic mapping and SN biopsy by Morton et al.,7 ELND was widely practiced for patients with intermediate-thickness primary melanomas, although no prospective randomized trial had ever shown (or has since shown) a significant overall survival benefit. The appropriate management strategy for patients with thick primary melanomas (4 mm) was even more uncertain, however, because all the randomized trials examining the efficacy of ELND had excluded patients with such tumors. As Essner et al. point out, there was a widespread belief that the risk of occult distant metastasis was so high in these patients that ELND could not be justified, even if it prevented troublesome problems in the regional lymph node field at a later date because long-term survival was expected in so few of the patients.
Whether the procedure of lymphatic mapping and SN biopsy, with CLND if a positive SN is found, will influence the survival outcome for patients with intermediate-thickness and thick primary melanomas is at present unknown. The results of large prospective randomized trials examining this question are awaited with great interest. What is already clear, however, is that lymphatic mapping with SN biopsy provides very important prognostic information in patients with intermediate-thickness primary melanomas, and on the basis of most of the studies published to date and our own previously unpublished data from the SMU, it seems that the same holds true for patients with thick primary melanomas. Essner et al., on the basis of their results, conclude that this may not be the case and suggest that because of the potentially high risk for patients with thick primaries to harbor occult distant metastases, lymphatic mapping and SN biopsy may not be warranted for patients with thick primaries, as the staging of the regional lymph nodes may not be predictive of clinical outcome. However, on the basis of the other studies already mentioned in this editorial, and our own results from the SMU, we suggest that the prognostic information obtained from SN biopsy for patients with thick primary melanomas is likely to be useful, not only for more focused patient selection for adjuvant therapy trials but also so that individual patients can be better informed of their likely prognosis. Clearly further studies in larger numbers of patients with longer periods of follow-up are required to provide more definitive answers to the important questions raised in the article by Essner et al., relating to the prognostic and clinical significance of regional lymph node involvement in patients with thick primary melanomas.
Acknowledgments
The authors thank Marjorie Colman for her expert assistance with data analysis.
Received for publication August 13, 2002. Accepted for publication August 20, 2002.
REFERENCES
4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002; 9: 754–61.This article has been cited by other articles:
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  R. E. Warner, M. J. Quinn, G. Hruby, R. A. Scolyer, R. F. Uren, and J. F. Thompson Management of Merkel Cell Carcinoma: The Roles of Lymphoscintigraphy, Sentinel Lymph Node Biopsy and Adjuvant Radiotherapy Ann. Surg. Oncol., September 1, 2008; 15(9): 2509 - 2518. [Abstract] [Full Text] [PDF]
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C. Caraco, U. Marone, E. Celentano, G. Botti, and N. Mozzillo Impact of False-Negative Sentinel Lymph Node Biopsy on Survival in Patients with Cutaneous Melanoma Ann. Surg. Oncol., September 1, 2007; 14(9): 2662 - 2667. [Abstract] [Full Text] [PDF]
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 J. N. Cormier, Y. Xing, M. Ding, J. E. Lee, P. F. Mansfield, J. E. Gershenwald, M. I. Ross, and X. L. Du Population-Based Assessment of Surgical Treatment Trends for Patients With Melanoma in the Era of Sentinel Lymph Node Biopsy J. Clin. Oncol., September 1, 2005; 23(25): 6054 - 6062. [Abstract] [Full Text] [PDF]
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T. M. Pawlik, M. I. Ross, and J. E. Gershenwald Lymphatic Mapping in the Molecular Era Ann. Surg. Oncol., April 1, 2004; 11(4): 362 - 374. [Full Text] [PDF]
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C. Caraco, E. Celentano, S. Lastoria, G. Botti, P. A. Ascierto, and N. Mozzillo Sentinel Lymph Node Biopsy Does not Change Melanoma-Specific Survival Among Patients with Breslow Thickness Greater than Four Millimeters Ann. Surg. Oncol., March 1, 2004; 11(3_suppl): 198S - 202S. [Abstract] [Full Text] [PDF]
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